NUEVOS FÁRMACOS Y ESTRATEGIAS EN EL CÁNCER DE PRÓSTATA. Joan Carles Servicio Oncología Médica Mr chairman ladies and gentlelmen its for me a great honor to have the opportunity to be here and share with you about angiogenesis and hormonoresistant prostate cancer.

CANCER DE PROSTATA AÑO 2005 EN EEUU DIAGNOSTICOS: 232.000 FALLECIMIENTOS 30.350

Actualmente ¿De qué disponemos ? Nuevos cistostáticos Satraplatino Epotilonas Abraxane Análogos Halichondrin B - SB-715992 Inhibidores Angiogénesis Avastin Talidomida/revimid Sunitinib Coxibs Oligonucleótidos antisentido Genasense Anti Clusterin OGX-011 Taxotere Y…. ? Vacunas GVAX Provenge After docetaxel chemotherapy how can we improve the results? In the last five years a lot of molecules are coming and increasing the armamentarium for prostate cancer treatment. Now we have novel chemotherapies, angiogenesis inhibitors, antisense oligonucleotides, Vaccines, Egfr inhibitors, bone targerts agents and vitamine D analogues. Most of this molecules are trying to combine with docetaxel. Análogos de Vit D Calcitriol Inhibidores de EGFR Erlotinib, Gefitinib 2C4 PDGF inhibitors Imatinib Agentes hueso diana Atrasentan Ibandronate/zoledronate Samarium Otros!

VACUNAS

INMUNOTERAPIA EN CANCER DE PROSTATA APC8015 (Provenge) Células dendríticas unidas a (FAP)GM-CSF GVAX.- Células alogénica de CP y que producen GM-CSF ONYVAXP.- Células alogénica de CP PROSTVAC.- Virus recombinante con copia de genes de PSA (+ inmunoestimulador)

ESTUDIOS FASE III VACUNAS

CITOSTÁTICOS

SATRAPLATINO Nuevo platino de administración oral. Actividad frente a células resistentes a taxanos, antraciclinas y otros derivados platínicos. Actividad en estudios de cáncer de próstata

Satraplatin and Prednisone Against Refractory Cancer Sternberg et al: SPARC Satraplatin and Prednisone Against Refractory Cancer Metastatic HRPC after 1 prior chemo (~50% prior docetaxel) Satraplatin 80mg/m2 po daily 1-5 q35d + Prednisone 5mg po BID Placebo po daily 1-5 q35d + Prednisone 5mg po BID 2:1 R A N D O M I Z E n=950 Primary Endpoint: PFS y OS Secondary Endpoints: TTP, PSA, Pain y ORR

Progression Free Survival 100 90 80 S P 70 Median (wks) 11.1 9.7 60 Survival Probability (%) HR: 0.67 (95% CI: 0.57 - 0.77) 50 Satraplatin + Prednisone Log-Rank P = 0.0000003 40 30 Placebo + Prednisone 20 10 10 20 30 40 50 60 70 80 90 Weeks

Halicondrin B analog (E7389, NSC 707389) in metastatic prostate cancer

IXABEPILONA (SWOG 0111) Uno de los primeros estudios realizados con estas drogas es el SWOG 0111 que evidenció. Estos resultados son similiares a los taxanos.

IXABEPILONA +/- EMP Galsky MD. J Clin Oncol. 2005;23(7):1439-46. Posteriormente a este estudio se realizó un estudio fase II aleatorizado que evidenció que la asociación a estramustina era factible y aumentaba la tasa de respuestas en estos enfermos. Galsky MD. J Clin Oncol. 2005;23(7):1439-46.

A retrospective evaluation of second-line chemotherapy response in hormone-refractory prostate carcinoma: second line taxane-based therapy after first-line epothilone-B analog ixabepilone (BMS-247550) therapy. Rosenberg JE, Galsky MD, Rohs NC et al. Cancer 2006;106(1):58-62 Conclusiones: El tratamiento empleando taxanos en segunda línea después de epotilonas provoca una elevada tasa de respuestas biológicas. Sin embargo aquellos enfermos que no experimentan una respuesta inicial a las epotilonas es poco probable que presenten respuesta a taxanos . Estos hallazgos son consistentes con una resistencia incompleta cruzada entre taxanos y epotilonas Además una de las ventajas de estos fármacos tal como hemos mencionado previamente no poseen resistencia cruzada con los taxanos. En este sentido aquí se muestran los resultados de los enfermos incluidos en el estudio previo y que recibieron taxanos (fundamentalmente docetaxel) cuando progresaron a epotilona.

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Rosenberg JE, Weinberg VK, Kelly WK et al. Cancer 2007 1;110(3):556-63.

The principal active metabolite of vitamin D Calcitriol The principal active metabolite of vitamin D Calcitriol, the principal active metabolite of vitamin D, has significant antineoplastic activity in pre-clinical models of prostate cancer and many other tumor types. Mechanisms by which calcitriol inhibits cancer cell proliferation and sensitizes cancer cells to cytotoxic agents remain incompletely understood. Calcitriol treatment has been associated with G0/G1 arrest, changes in p21Waf1 and p27Kip1 expression, dephosphorylation of the retinoblastoma protein, downregulation of bcl-2, inhibition of angiogenesis, and induction of apoptosis. Calcitriol-induced changes in several growth factor systems, including EGF, TGFß, and IGF have been reported. Calcitriol enhances the antitumor activity of several cytotoxic agents in a number of preclinical tumor model systems. In prostate cancer cell lines, calcitriol enhances antitumor activity of docetaxel, paclitaxel and platinum compounds especially through downregulation of bcl-2. Similar results are seen in prostate cancer animal models with docetaxel and paclitaxel.18-19

ASCO 2005

ASCENT study: Randomized study of Docetaxel +/-high-dose Calcitriol in HRPC (n=250 pts) Stratification Pain level PPI ≥ 2 or AS ≥ 10 vs. PPI < 2 or AS < 10 Karnofsky ≤ 70 vs. ≥ 80 Docetaxel 36 mg/m2 weekly 3 of 4 wks + DN-101 45 mg po daily Docetaxel 36 mg/m2 weekly 3 of 4 wks + Placebo Primary end point: PSA response ASCENT : Androgen-independent prostate cancer Study of Calcitriol Enhancing Taxotere 38 7

ASCENT Study: Survival Placebo DN-101 Probability of Survival 0.00 0.25 0.50 0.75 1.00 Weeks 12 24 36 48 60 72 84 23.5 mos Median Survival DN-101 23.5 mos (estimated) Placebo 16.4 mos (observed) 16.4 mos 7.1 months A 900 pt confirmatory trial is planned Decreased GI and Thrombembolic toxixcity- unclear why vit d analogues rfuce tissue facto Hazard Ratio (95% CI) Unadjusted 0.70 (0.48 – 1.028), P = 0.070 Multivariate 0.67 (0.45 – 0.97), P = 0.035 Beer T, ASCO 2005

Primary end point: Overall Survival ASCENT II study: Phase III study of Docetaxel +/-high-dose Calcitriol in HRPC (n=900) RANDOMI ZE Docetaxel 36 mg/m2 d2, weekly 3 of 4 wks + DN-101 45 µg po daily Docetaxel 75 mg/m2 every 3 weeks + prednisone 200 sites activated 1/ 2006 Secondary Endpoints: SRE rate TE rate GI rate Overall safety Primary end point: Overall Survival Secondary Endpoints: SRE rate, TE rate, GI rate, Overall safety 7 38

ENSAYOS ANTIANGIOGÉNICOS PRIMERA GENERACIÓN: Suramina. Talidomida. TNP 770 SEGUNDA GENERACIÓN: Inhibidores de la matriz metaloproteasa. TERCERA GENERACION: Panzem (2 metoxiestradiol) VEGF / Inhibidores de VEGFR. Inhibidores de adhesión celular. Inductores de colapso vascular

A couple of years ago a very elegant study by Cox et al reported diffferent antiangiogenic agents to be used in hormonoresistant prostate cancer as you can see in this slide. The author tried to classify different compount in four groups.

Thalidomide: in the clinic and the laboratory Randomized phase II trial of thalidomide in patients with androgen-independent prostate cancer (AIPC) . 2 doses of thalidomide N = 50 pts low-dose arm . 200 mg/d 13 pts high-dose arm 200 mg/d escalated to 1200 mg The high-dose arm was terminated early (side effect profile: sedation and fatigue) 18% (low dose arm) 50% or greater decline in PSA Thalidomide has been studied in the clinic using two treatment doses in a randomized phase II trial. In this study patients treated with high doses had a lot of side effects mainly sedation and fatigue. Patients treated with low doses had an eighteen percent PSA response. Figg W, CCR 2001

DOCETAXEL + THALIDOMIDE Randomized Phase II study DOCETAXEL 30 mg/m2 Q week x 3 of 4 Thalidomide 200 mg daily N=50 N=75 Primary endpoint PSA Response Rate Dahut studied the combination of docetaxel plus thalidomide vs docetaxel alone in a randomized phase II trial. The schedule from docetaxel was three times every four weeks. In this study 75 patients had been included. DOCETAXEL 30 mg/m2 Q week x 3 of 4 N=25 Dahut WL, Figg WD

In this study there were no difference in relation to PSA decline, soft tissue response o time to progression However patients with the variant of cyp2c19 had a lower capability to metabolize the thalidomide and and exhibited a decrease response rate. Patients with the variant CYP2C19 genotype would form less of the active metabolite, thus exhibiting a decreased clinical response (as assessed by a decline in PSA)

THALIDOMIDE y DOCETAXEL Después 46.7 meses de seguimiento: la supervivencia media en el grupo de docetaxel fue de 14.7 meses frente a 25.9 meses para el grupo de combinación (P .041) However after fouty six months of follow-up. Median survival time for docetaxel was 15 months and 25 months for the combination. One finding of concern was the incidence of thromboembolic events in the combination arm. Las principales toxicidades fueron: Astenia, hiperglicemia y trastornos ungueales. El grupo de combinación destacó por un mayor número de episodios tromboembólicos.

Bevacizumab monotherapy in prostate cancer 1 patient PSA decrease > than 25% 3 patients PSA response < than 25% No patients had a greater than 50% decrease of PSA. Conclusion: bevacizumab alone in metastatic disease did not produce significant response Another antiangiogenic molecule is bevacizumab that has demostrated activity in breast, lung, colon and renal cancer. In prostate cancer has little efficacy as monotherapy as you can see from this study reported Reese et al. 15 patients has been treated with this antibody but none has had a biological partial responses. Reese D, Proc ASCO1999,18:1355 The Prostate Journal, 3;65-70,2001

Treatment (Estramustine no longer included in the treatment regimen) Docetaxel/Bevacizumab/Estramustine Study Design Treatment (Estramustine no longer included in the treatment regimen) Dexamethasone 8 mg po bid Days 1–3 Cycle repeats q3 weeks Day 1 2 3 4 5 6 7 Docetaxel 70 mg/m2 iv Day 2 Bevacizumab 15 mg/kg over 90 min Day 2 Estramustine 280 mg po tid Days 1–5 Another study reported by Picus in ASCO combined docetaxel, beva and estramustine for five days every 21 days cycle. Picus J, et al. Proc Am Soc Clin Oncol 2003;22:393 [abstract & poster 1578]

Survival and TTP Results (n=78) PSA progression only 47/75 progressed so far media 9.7 months median number of cycles : 8 (range 1-30) Response rates -PSA responses: 79% (59/75) -> >50% decline from baseline -Of 36 patients with measurable disease – 15 PR (42% measurable disease response rate) 32% also had stable disease for > 6 weeks Median survival: 21 months In this study they reported an 80% PSA response rate with a 42% response rate from measurable disease with a median survival of 21 months Picus J, et al. Antiangiogenic Symp 2006

Primary end point is PFS In this phase III study patients are stratified according to the Halabi nomogram and the primary end point is progression free survival. Primary end point is PFS

VEGF Trap is a Unique VEGF Blocker “Trap technology” Increased affinity for VEGF Binds to VEGF-A, VEGF-B and PlGF (Trapping of circulating VEGF) Capable of animal xenograft tumor regression Potential for subcutaneous administration Kd ~0.5 pM

EFC6546: VENICE Study (Start this year) Multicenter, double blind, randomized study EFC6546: VENICE Study (Start this year) R A N D O M I Z E Aflibercept 6mg/kg IV over 1hr, day 1 TXT 75mg/m² , day 1 Prednisone 10mg/day, continuously q 3 weeks m HRPC Stratification factor: ECOG PS (0,1 vs 2) 1190 pts/ 200 sites Placebo, day 1 TXT 75mg/m² , day 1 Prednisone 10mg/day, continuously q 3 weeks This molecule will be studied in prostate cancer in a phase III study that will include 1200 patients with metastatic hormonoresistant prostate cancer. Patients will be stratified according to performance status. The primary end point of the study will be survival. The secondary end points will be Pain, disease free survival and quality of life. 3 years accrual expected. 1st: Overall Survival: 20% risk reduction of death. From 19 to 24 months. Interim analysis at 647 death (862 events required overall) 2nd: Pain, PSA, QoL, DPFS Treatment until PD, consent withdrawn, or unacceptable toxicity. Follow up until death

Endotelinas y cáncer de próstata La endotelinas se expresan en las células del cáncer de próstata ET-1 aumenta a medida que la célula se hace androgenoindependiente. La expresión del receptor ETA-aumenta a medida que aumenta el grado2,3 Las endotelinas favorecen el aumento del depósito óseo4,5 Going to present data from a large Phase II study of Atrasentan (an endothelin antagonist) Before describing the structure of the trial a little background on endothelin and why the ET axis should be targeted in HRPCa 1Nelson et al. Nature Medicine, 1995 2Nelson et al. Cancer Res, 1996 3Gohji et al. J Urology, 2001 4Nelson et al. Urology, 1999 5Nelson et al. Prostate Journal, 1999

Biología de las Endotelinas Cell ETA Síntesis matriz ET-1 Efectos circulatorios Vasoconstricción Angiogénesis The endothelin axis is a novel target in cancer, and the data I am going to show is the first communicated data on the effects of endothelin blockade on cancer in humans. endothelins are a family of 4 peptide hormones produced by endothelial cells and have a variety of autocrine and paracrine functions. ET-1, the most active of the family; functions are primarily mediated through ET-A receptors. ET-1 is the most potent vasoconstrictor in the human body; endothelin axis has been studied extensively in disease states such as hypertension, CHF and pulmonary hypertension. ET-1 also promotes cell proliferation and survival. In the vasculature these actions promote angiogenesis . In the bone, these effects are selective for osteoblasts, promoting osteoblast proliferation and maturation. The net effect of too much endothelin in bone is excessive new bone formation. experimental evidence, shows that ET-1 plays a key role in osteoblastic metastases in prostate cancer. In some model systems ET-1 appears to mediate pain, and it also promotes matrix synthesis. Proliferación y supervivencia celular Efectos Nociceptivos Efectos osteoblásticos remodelación ósea dolor

Atrasentan Dosis única diaria Administración oral OCH3 HCI N COOH O Atrasentan – the chemical structure of which is shown here is an ideal compound to explore the utility of ET antagonists in prostate cancer First, atrasentan is Extremely potent with a Ki in the picomolar range .10 –15 Second it is extremely selective for the ET-A receptor, which should potentially lessen side effects.Over 1800 fold more selective for A relative to B Orally bioavailable so can be given in pill form 25 hour half-life ideal for once a day dosing Abbott, just like everyone else in the ET field began its development program with a focus on cardiovascular disease. Because of this, atrasentan’s early phase clinical development looks a little different than that of other anti-cancer agents. 18 phase I studies have been performed, 11 in healthy volunteers, 1 in CHF, 1 in renal insufficiency, and 5 in cancer patients. Doses ranged from .2 to 139.5 mg in healthy volunteers and from 2.5 mg to 95 mg in cancer patients. Side effect profiles were similar in healthy subjects and cancer patients with HA, being dose-limiting in both populations. Interestingly, in the healthy volunteers, this HA was intolerable at 30mg whereas, cancer patients tolerated doses as high as 75 and 95 mg.

Atrasentan retrasa el tiempo de progresión de PSA 1.0 0.8 0.6 0.4 0.2 Probability of no disease progression A similar adavntage of Atrasentan over Placebo was also seen in the time to PSA progression, however here the benefit was more pronounced in the 10 mg group then in the 2.5 mg group 0 100 200 300 400 500 Dias desde aleatorización *PSA progression = 2 consecutive values 50% ³baseline

A phase 3 randomized controlled trial of efficacy and safety of atrasentan in men with metastatic-hormone-refractory prostate cancer. Carducci MA, Saad F, Abrahamsson PA et al. Cancer 2007;Sep 20  Atrasentan Phase III data from Study M00-211 in end-stage prostate cancer patients (M1). 810-patient, multi-national, double blind placebo-controlled clinical study (atrasentan versus placebo), reviewed by an IDMC, improvement in: development of bone pain as an adverse event, prostate-specific antigen (PSA) levels, biochemical markers of skeletal progression   The study did not meet its primary endpoint of time-to-disease progression, ( trial stopped). Además una de las ventajas de estos fármacos tal como hemos mencionado previamente no poseen resistencia cruzada con los taxanos. En este sentido aquí se muestran los resultados de los enfermos incluidos en el estudio previo y que recibieron taxanos (fundamentalmente docetaxel) cuando progresaron a epotilona. 72

Another phase III study conducted by the SWOG is the combination of docetaxel prednisone with or without atrasentan. Patients would be stratified according to type of progression, pain, extraskeletal disease and biphosponates.

Sorafenib trials in Prostate Chi Esmo 2006. Sorafenib (min activity PSA based,28pt) Steinbild ASCO 2006 Phase II study of Sorafenib (BAY 43-9006) in hormone-refractory patients with prostate cancer: A study of the Central European Society for Anticancer Drug Research--EWIV (CESAR). 55 pts ,42 pts evaluable for PP-TTP-12, 2 pts (4.8%) had a response and 15 pts (35.7 %) showed SD >12 weeks and 25 pts (59.5 %) showed PD. Dahut ASCO 2006, improvement in bone scans in the absence of any prostate-specific antigen responses. Three studies has been reported on prostate cancer showing minor activity of sorafenib. However a very high percentage of patients experienced stabilization of the disease in a similar way as in renal cell carcinoma.

Metronomic chemotherapy Metronomic chemotherapy regimens differ from the standard maximum tolerated dose (MTD) chemotherapy regimens that have been common practice in medical oncology for decades. a | In standard chemotherapy, a drug is typically given in a single bolus injection or infusion at the MTD, interspersed by a long break — for example, 3 weeks — before the next course of this therapy is administered. Doses that exceed the MTD (‘high-dose’ chemotherapy) must be accompanied by an autologous bone-marrow stem-cell transplant and supportive-care growth-factor drugs to prevent lethal bone-marrow failure. In b and c, examples of metronomic chemotherapy regimens are shown where, for example, the chemotherapy drug is administered more frequently, such as weekly (b) or daily (c), with no prolonged drug-free interruptions. Drugs that can be administered orally, such as cyclophosphamide, capecitabine, etoposide (VP-16), UFT (uracil plus tegafur, a fluoropyrimidine antimetabolite), would be ideal for prolonged daily administration schedules. Omission of prolonged drug-free periods is a key aspect of the basis for the anti-angiogenic effects of lowdose metronomic chemotherapy regimens, as these breaks allow repair and recovery from the anti-angiogenic effects of chemotherapy drugs on developing tumour blood vessels. Endothelial cells are sensitive to the action of conventional cytotoxic drugs, if the dosing regimen is altered (metronomic Ch). most standard chemotherapies likely target the proliferating endothelial cells in tumors, rest periods in traditional MTD regimens are thought to allow the endothelial cells to recover by using their intact p53-based damage sensor The incorporation into metronomic chemotherapy regimens of antiangiogenic drugs, enhance efficacy in preclinical models Metronomic chemotherapy Refers to the close, regular administration of comparatively low doses of cytotoxic drugs, over prolonged periods It is thought to have an antiangiogenic basis

Carles J et al. BJC (in press) Weekly Administration of Docetaxel in Combination with Estramustine and Celecoxib in Patients with Advanced Hormone-Refractory Prostate Cancer: A Phase II Study Age years Median 67 Range 48-78 Karnosfky IK 80 17 <80 10 Prior treatments Prostatectomy 16 Radiotherapy 26 Hormonal therapy 48 # of previous hormonal treatments 1 19 2 >2 13 Tumor stage II 11 III 8 IV 29 Sites of disease Bone 42 Soft Tissue 15 Lymph node Liver 3 Lung # disease lessions 1 2 9 >2 28 We have performed a phase II study combining docetaxel, estramustine and celecoxib. Patients characteristics are shown in this slide. I would like to point out that 2/3 of the patients had received more that wone line of hormonal treatment and 60% of patients had more than two metastatic lessions. Treatment was administered as an outpatient manner. Docetaxel was administered on day 2,9 and 16. Estamustine on day 1 to 3, 7-10 and 15-17. Celecoxib was administered at 400 mg to times a day continously. Carles J et al. BJC (in press)

Carles J et al .BJC in press Weekly Administration of Docetaxel in Combination with Estramustine and Celecoxib in Patients with Advanced Hormone-Refractory Prostate Cancer: Final Results from a Phase II Study Time to Progression Overall Suvival We have observed a time to progression of with a median survival time of…….. months months Carles J et al .BJC in press

Grade 3/4 treatment-related toxicity (n=48) Toxicity was mild and manejable Carles J et al .BJC in press

RECEPTOR ANDRÓGENOS MUTACIONES RECEPTOR - LIGANDO AMPLIFICACIÓN GEN TRANSACTIVACIÓN RECEPTOR Factores de crecimiento Citoquinas Otros coactivadores Tal como he mencionado con anterioridad el receptor de androgenos se expresa de una forma constrante a lo largo de toda la enfermedad. Se han implicado distintas alteraciones a nivel del receptor como son:

HER-2/neu - Receptor andrógenos PI3K PTEN MAPK Akt/PKB AR AR La respuesta a esta pregunta parece ser que si, Her 2 seria capaz de interrelacionarse con el receptor de androgenos y provocar su estimulación a trave´s de las dos vias más importantes:tanto MAP kinasa como Akt P213 P791 AR AR AR Supervivencia/Proliferación

CONCLUSION: Pertuzumab has no clinically significant single-agent activity in castrate patients with HRPC at either of the tested dose levels. This may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.

OTROS MECANISMOS BIOLOGICOS DE ACTUACIÓN

Inhibidores Histona Principales agentes: SAHA, LAQ 824 Inductores de p21. Efectos potenciales para la diferenciación, inhibición del crecimiento y efectos antiangiogénicos Regulación del R Andrógenos

TELOMERASAS Diana universal en oncología con elevada especificidad tanto para stem cell como para células tumorales diferenciadas. Inhibidores pueden provocar respuesta clínica rápida especialmente en combinación con fármacos citotóxicos o radioterapia.

CHAPERONAS SE ASOCIAN A ENFERMEDADES DEGENERATIVAS Y CANCER ANTIAPOPTÓTICAS INHIBIDORES POTENTES DE LA DEGRADACION DE PROTEINAS PRODUCIDAS EN SITUACIONES DE STRESS

IGF-IR Vías antiapoptoticas Se trata de una vía muy importante para ser empleada en el tratamiento de esta enfermedad. Es un poco prematuro definir cuando se empleará debido a que se deben realizar estudios fase II. La toxicidad de los fármacos en desarrollo es escasa.

Proteasome 20S core catalytic complex 19S regulatory subunit Large, multiprotein particle composed of 2 functional components: 20S core catalytic complex 19S regulatory subunit The 20S complex is formed of 4 multiprotein rings: outer  subunit rings central  subunit rings (catalytic chamber) The proteasome degradates short-live proteins regulating many important cellular processes Leukemia 2002 PHASE I/II TRIAL OF BORTEZOMIB (PS-341) PLUS DOCETAXEL IN PATIENTS WITH ADVANCED ANDROGEN-INDEPENDENT PROSTATE CANCER. B. J. Roth, (33% PSA RR). ASCO 2003. Abs 1705 Price N, Dreicer R. Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer.Clin Prostate Cancer. 2004 3:141-3

CONCLUSIONES “Live with cancer – not die from it” SE TRATA DE UN TUMOR CON IMPLICACIONES SOCIOSANITARIAS. CINÉTICA Y TROFISMO CELULAR CARACTERÍSTICOS. RELACIÓN CÉLULA TUMORAL - ENTORNO METABÓLICO ÓSEO. DESARROLLO PROGRAMAS DE FARMACOGENÓMICA. IMPORTANCIA DE NUEVAS COMBINACIONES BASADAS EN EL CONOCIMIENTO DEL ESTADO DE LA ENFERMEDAD. “Live with cancer – not die from it”